Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine

ABSTRACT

The present invention describes specific crystalline forms of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl-phenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.

FIELD OF THE INVENTION

The present invention is directed to crystalline forms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, methods of making the same, pharmaceutical compositionscomprising the same and methods of treatment using the same.

BACKGROUND

Polymorphism denotes the existence of more than one crystalline form ofa substance. This ability of a chemical substance to crystallize in morethan one crystalline form can have a profound effect on the shelf life,solubility, formulation properties, and processing properties of a drug.In addition, the action of a drug can be affected by the polymorphism ofthe drug molecule. Different polymorphs can have different rates ofuptake in the body, leading to lower or higher biological activity thandesired. In extreme cases, an undesired polymorph can even showtoxicity. The occurrence of an unknown crystalline form duringmanufacture can have a significant impact.

Understanding and controlling polymorphism, then, gives a decidedadvantage in bringing new drugs to the marketplace. First and foremost,predicting any possible polymorphs for a drug product can be used todiminish the possibility of contamination during a drug's manufacture orstorage by other polymorphic forms. Failure to catch contamination canhave life-threatening consequences in some cases. Crystallizing anunintended polymorph during manufacture can mean weeks or even months ofproduction downtime while scientists find and correct the cause of thenew crystalline form or go through another round of testing to obtainapproval for the new crystalline form.

Second, understanding which crystalline forms of a drug are possible incertain cases allows researchers to maximize the desired properties of acompound, such as solubility, formulation properties, processingproperties, and shelf life. Understanding these factors early in thedevelopment of a new drug may mean a more active, more stable, or morecheaply manufactured drug.

The compound5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, in the form of a free base, of formula

is an anaplastic lymphoma kinase (ALK) inhibitor, a member of theinsulin receptor super family of receptor tyrosine kinases. Compound Iwas originally described in WO 2008/073687 A1 as Example 7, compound 66.

WO 2008/073687 A1, however, provides no information about crystallineforms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine or its corresponding salts. Crystalline forms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine have been discovered, which are useful in treating diseaseswhich respond to inhibition of anaplastic lymphoma kinase activity,focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70(ZAP-70) insulin-like growth factor (IGF-1R or a combination thereof.The crystalline forms exhibit new physical properties that may beexploited in order to obtain new pharmacological properties, and thatmay be utilized in the drug product development of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

SUMMARY OF THE INVENTION

The present invention provides substantially pure crystalline forms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

The present invention also provides a pharmaceutical compositioncomprising: (a) a therapeutically effective amount of a substantiallypure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine; and (b) at least one pharmaceutically acceptable carrier.

The present invention also provides a method for the preparation of asubstantially pure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine which comprises the step of: reacting5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine dihydrochloride in a solvent with at least two equivalents ofaqueous sodium hydroxide.

The present invention also provides a method for the preparation of asubstantially pure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine which comprises the step of: heating a mixture of twocrystalline forms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine in a solvent.

The present invention also provides a method for the treatment ofdisorders mediated by anaplastic lymphoma kinase, comprisingadministering to a patient in need of such treatment an effective amountof a substantially pure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

The present invention also provides the use of a substantially purecrystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine for the preparation of a medicament for the treatment ofdisorders mediated by anaplastic lymphoma kinase.

The present invention also provides a method for the treatment ofdisorders selected from benign or malignant tumor; a cancer selectedfrom anaplastic large cell lymphoma; non-Hodgkin's lymphoma; aninflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung,non-small cell lung cancer; bronchus; prostate; breast (includingsporadic breast cancers and sufferers of Cowden disease); pancreas;gastrointestinal cancer; colon; rectum; colon carcinoma; colorectaladenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenalgland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma;kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix;vagina; ovary; multiple myeloma; esophagus; a leukaemia; acutemyelogenous leukemia; chronic myelogenous leukemia; lymphocyticleukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavityand pharynx; larynx; small intestine; and melanoma, comprisingadministering to a patient in need of such treatment an effective amountof a crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts X-ray powder diffraction pattern for crystalline form Aof5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

FIG. 2 depicts the differential scanning calorimetry curve forcrystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

FIG. 3 depicts the thermogravimmetric plot for crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

FIG. 4 depicts X-ray powder diffraction pattern for crystalline form Bof5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

FIG. 5 depicts the differential scanning calorimetry curve forcrystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

FIG. 6 depicts the thermogravimmetric plot for crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

DETAILED DESCRIPTION OF THE INVENTION

The compound5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is obtained in distinct crystalline forms. These “crystallineform(s)” (or “crystalline modification(s)” or “polymorphic form(s)” or“polymorph(s)”, as the terms will be used interchangeably herein) differwith respect to thermodynamic stability, physical parameters, x-raystructure and methods of preparation. In addition, “amorphous” refers toa disordered solid state. It should be noted that different samples of aparticular crystalline form will share the same major X-ray powderdiffraction (XRPD) peaks, but that there can be variation in powderpatterns with regard to minor peaks. In addition, the term “about” withregard to XRPD maxima values (in degrees) generally means within 0.3°,more preferably within 0.2°, and most preferably within 0.10 of thegiven value. Alternatively, the term “about” means (in this and allcontexts) within an accepted standard of error of the mean, whenconsidered by one of ordinary skill in the art. As used herein, the term“substantially pure” means that more than 80% of one crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine or salt thereof is present or isolated, preferably at least85%, more preferably at least 90%, and most preferably at least 95% ofone of the crystalline forms described herein is present.

In one embodiment, a substantially pure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is isolated, referred to as crystalline form A. Form A of thefree base is relatively non-hygroscopic at 84% relative humidity (RH)and exhibits minor increase in moisture uptake at 93% RH. It has goodsolubility at pH 1, fair solubility in water and good solubility inorganic solvents (11 mg/mL in pH 1, 0.21 mg/mL in water and 40 mg/mL inmethanol, respectively). It is converted to a hydrochloride salt(non-stoichiometric) in pH 1 (0.1N HCl) solution over 72 hour. The pH of1% suspension in water is 6.86.

The XRPD of crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits diffraction peaks having maxima at diffraction angles7.2°, 8.1°, 10.8°, 12.0°, 12.4°, 13.4°, 14.4°, 14.8°, 15.7°, 16.9°,17.7°, 18.5°, 19.0°, 19.5°, 20.0°, 20.3°, 21.1°, 21.6°, 22.4°, 22.6°,23.0°, 24.1°, 24.5°, 25.5°, 26.0°, 26.2°, 27.0°, 27.3°, 28.3°, 29.0°,29.1°, 30.6°, 31.3°, 32.8°, 33.5°, 34.2° and 36.4° (2θ degrees), assummarized by the XRPD pattern in FIG. 1.

Crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits the following thermal parameters: melting point, Tm(onset) 174° C. as determined by differential scanning calorimetry at ascanning rate of 10° C./min. (FIG. 2), decomposition point, T>250° C.,and a weight loss on drying of 0.1% at 200° C., as determined bythermogravimmetric analysis and summarized in FIG. 3.

The Fourier Transform Infrared (FT-IR) spectrum of crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits main bands (in units of wavenumbers, cm⁻¹) at 3440.4,3318.9, 2973.7, 2931.3, 2921.7, 1596.8, 1562.1, 1498.4, 1442.5, 1409.7,1382.7, 1311.4, 1284.4, 1270.9, 1251.6, 1224.6, 1139.7, 1126.2, 1126,1126.2, 1105.0, 1081.9, 1049.1, 1020.2, 1012.5, 952.7, 937.3, 894.8,877.5, 860.1, 848.5, 817.7, 798.4, 781.0, 763.7, 756.0, 732.8, 686.6,665.3, 644.1, 586.3 and 543.8.

In another embodiment, a substantially pure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is isolated, referred to as crystalline form B.

The XRPD of crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits diffraction peaks having maxima at diffraction angles5.1°, 5.5°, 5.6°, 9.5°, 9.6°, 10.1°, 11.0°, 11.8°, 12.1°, 12.6°, 13.7°,14.5°, 14.9°, 15.2°, 16.1°, 16.6°, 16.7°, 17.0°, 17.1°, 17.5°, 17.7°,18.0°, 18.8°, 19.0°, 19.3°, 19.5°, 20.5°, 20.9°, 21.5°, 21.9°, 22.1°,22.4°, 22.8°, 23.2°, 23.7°, 23.9°, 24.3°, 24.5°, 24.8°, 25.1°, 25.4°,25.9°, 26.4°, 26.8°, 27.8°, 28.1°, 28.6°, 29.1°, 29.6°, 29.8°, 30.6°,31.6°, 32.7°, 33.5°, 34.2°, 35.4°, 35.6° and 36.8° (2θ degrees), assummarized by the XRPD pattern in FIG. 4.

Crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits the following thermal parameters: melting point, Tm(onset) 162° C. as determined by differential scanning calorimetry at ascanning rate of 10° C./min. (FIG. 5), decomposition point, T>250° C.,and a weight loss on drying of 0.05% at 200° C., as determined bythermogravimmetric analysis and summarized in FIG. 6.

The Fourier Transform Infrared (FT-IR) spectrum of crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine exhibits main bands (wavenumbers, cm⁻¹) at 3418.7, 3309.5,3202.3, 2976.2, 2936.3, 2806.9, 2731.8, 1683.9, 1652.8, 1598.4, 1568.9,1507.0, 1483.5, 1447.1, 1411.0, 1314.9, 1288.1, 1261.1, 1220.8, 1195.7,1170.8, 1140.1, 1124.6, 1083.2, 1053.3, 1010.1, 947.1, 874.5, 776.0,758.7, 734.5, 706.5, 678.5, 652.1, 586.3, 544.7, 519.1, 472.6, and456.8.

In an exemplary embodiment, the present invention provides a method forthe preparation substantially pure crystalline forms of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine. The crystalline forms are prepared from a solvent or mixedsolvents comprising a good solvent, in which the compound is readilysoluble, and a poor solvent, in which it is more sparingly soluble, mayalso be employed provided that crystallization from the mixture ispossible using the selected solvent mixture. Examples of good solventsinclude methanol, ethanol and isopropanol, formic acid, acetic acid,ethyl acetate, tetrahydrofuran and acetone. An example of a poor solventis e.g., water.

In one embodiment, crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is prepared by reacting5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine dihydrochloride in aqueous acetone with at least twoequivalents of aqueous sodium hydroxide. The ratio of acetone:waterusefully employed in accordance with the invention ranges from 1:1 to5:1 and 1:1 to 1:5 (volume:volume, v/v), including 1:1 and 3:1. Thereaction temperature ranges from 20° to 70° C., including 55° C.

In one embodiment, the crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine contains less than 1% by weight total impurities. In anotherembodiment, the polymorph form A contains less than 0.5% by weight totalimpurities. In yet another embodiment, the polymorph form A containsless than 0.1% by weight total impurities.

In another embodiment, crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is prepared by reacting5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine with aqueous hydrochloric acid and subsequently adding sodiumhydroxide. The reaction temperature ranges from 20° C. to 70° C.

In another embodiment, crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is converted to crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine by adding a small amount of crystalline form A (1% by weightor less, referred to as seeding) to a suspension or solution of form Bof5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine in aqueous acetone. The temperature usefully employed forseeding ranges from 20-40° C.

As used herein, the term “seed” can be used as a noun to describe one ormore crystals of a crystalline compound of formula I. The term “seed”can also be used as a verb to describe the act of introducing said oneor more crystals of a crystalline compound of formula I into anenvironment (including, but not limited to e.g., a solution, a mixture,a suspension, or a dispersion) thereby resulting in the formation ofmore crystals of the crystalline compound of formula I.

In another embodiment, crystalline form B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is converted to crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine by heating a suspension or solution containing crystallineform B of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine in aqueous acetone. Mixed solvents usefully employed include,for example, acetone/water and ethanol/water. In a preferred embodiment,the ratio of acetone:water usefully employed ranges from 1:1 to 5:1(volume:volume, v/v), including 1:1 and 3:1. The reaction temperatureranges from 30° to 70° C., including 50° C.

In an exemplary embodiment, a pharmaceutical composition is providedcomprising: (a) a therapeutically effective amount of a substantiallypure crystalline form of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine; and (b) at least one pharmaceutically acceptable carrier. Ina preferred embodiment, the pharmaceutical composition comprises: (a) atherapeutically effective amount of a substantially pure crystallineform A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine; and (b) at least one pharmaceutically acceptable carrier.

The at least one pharmaceutically acceptable carrier is in the form of adiluent, vehicle or excipient and can readily be selected by one ofordinary skill in the art and will be determined by the desired mode ofadministration. Illustrative examples of suitable modes ofadministration include oral, nasal, parenteral, topical, transdermal,and rectal. The pharmaceutical compositions of this invention may takeany pharmaceutical form recognizable to the skilled artisan as beingsuitable. Suitable pharmaceutical forms include solid, semisolid,liquid, or lyophilized formulations, such as tablets, powders, capsules,suppositories, suspensions, liposomes, and aerosols.

In an exemplary embodiment, use of a substantially pure crystalline formof 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine for the preparation of a medicament for the treatment ofdisorders mediated by anaplastic lymphoma kinase is provided. In apreferred embodiment, the medicament comprises: (a) a therapeuticallyeffective amount of a substantially pure crystalline form A of5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine. The medicament is useful in treating diseases which respondto inhibition of anaplastic lymphoma kinase activity, focal adhesionkinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70)insulin-like growth factor (IGF-1R and combinations thereof. Thediseases are selected from benign or malignant tumor; a cancer selectedfrom anaplastic large cell lymphoma; non-Hodgkin's lymphoma; aninflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung;bronchus; prostate; breast (including sporadic breast cancers andsufferers of Cowden disease); pancreas; gastrointestinal cancer; colon;rectum; colon carcinoma; colorectal adenoma; thyroid; liver;intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric;glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis;urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiplemyeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronicmyelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; acarcinoma of the brain; oral cavity and pharynx; larynx; smallintestine; and melanoma. A “therapeutically effective amount” isintended to mean the amount of the inventive crystalline form that, whenadministered to a subject in need thereof, is sufficient to effecttreatment for disease conditions alleviated by the inhibition of proteinkinase activity. The amount of a given compound of the invention thatwill be therapeutically effective will vary depending upon factors suchas the disease condition and the severity thereof, the identity of thesubject in need thereof, etc., which amount may be routinely determinedby artisans of ordinary skill in the art. Preferably, more than 80%,more preferably at least 85%, still more preferably at least 90%, andmost preferably at least 95%, of the crystalline form administered is ofone of the inventive forms. As noted above, illustrative modes ofadministration include oral, nasal, parenteral, topical, transdermal,and rectal. Administration of the crystalline form may be accomplishedby administration of a pharmaceutical composition of this invention orvia any other effective means.

Specific embodiments of the invention will now be demonstrated byreference to the following examples. It should be understood that theseexamples are disclosed solely by way of illustrating the invention andshould not be taken in any way to limit the scope of the presentinvention.

Example 1 Preparation of Form A of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2(isopropylsulfonyl)phenyl)-2,4-diamine

5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diaminedi-hydrochloride salt

The compound 2-isopropoxy-5-methyl-4-(piperdin-4-yl) anilinedihydrochloride (33.00 g, 85.25 mmol) and 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (32.53 g) was added to a 3-necked500-mL round-bottomed flask equipped with mechanical stirring,thermocouple, reflux condenser and N₂ inlet-outlet. A solvent,2-propanol (255.0 g, 325 mL), was added and the mixture to heated toreflux at 82±2° C. and stirred for at least 14 hours. The mixture wascooled to 22±3° C. over 1 hour and stirred at 22-3° C. for 3 hours. Theresulting solids were filtered and rinsed with 3×40 g (3×51 mL) of2-propanol. The solids were dried at 50±5° C./10 mbar for 16 hours toyield 44.63 g of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diaminedi-hydrochloride salt. Chemical Purity (as determined by HPLC): 97.3%.Corrected yield: 71.6%. LOD=11.60%. The dihydrochloride salt wasrecrystallized using acetone:water (10:1, v/v). Chemical Purity (asdetermined by HPLC): 98.8%.

Form A of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine

7.00 g of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N-(2-(isopropylsulfonyl)phenyl)-2,4-diamine di-hydrochloride and21.0 g of acetone:water (3:1, v/v) was added to a dry and cleancrystallizer at ambient temperature. The mixture was heated to 55±3° C.in about 20 minutes to obtain a clear solution. The hot solution wasfiltered and 2.6 g of acetone and water was added to the mixture. Whileheating was maintained, 14.69 g (about 58% by weight) of aqueous NaOHsolution was added over a period of about 0.5 hour. The reaction mixturewas maintained at 55±3° C. for an additional 2 hours to yield anoff-white slurry. An additional 10.82 g (about 58% by weight) of aqueousNaOH solution was added to the hot solution over a period of 1.5 hoursto yield a thick off-white slurry. The slurry was cooled to 20±3° C.over a period of about 45 minutes and 47.0 g of deionized (DI) water wasadded over about 30 minutes and the off-white slurry was stirred at20±3° C. for 1 hour. The slurry was filtered and rinsed with 2×25.0 g ofDI water. The wet cake was dried about 17 hours in a vacuum oven at50±3° C. and 10 mbar under a N₂ purge to yield 6.06 g off-white or tansolid, 5.30 g of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N-(2-(isopropylsulfonyl)phenyl)-2,4-diamine. Yield: 87.5%. FormA was identified and confirmed by its corresponding XRPD pattern, FT-IRand thermal parameters.

Example 2 Preparation of Form B of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine

5.58 g of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N-(2-(isopropylsulfonyl)phenyl)-2,4-diamine was dissolved in 50mL of 1.0 N HCl at 30-40° C. to afford a clear solution. 200 mL of 0.3 NNaOH was added this clear solution dropwise over 20 minutes at 20-23° C.A cloudy mixture was obtained, which was heated with stirring at 40-42°C. for 2 hours and subsequently heated to 50-55° C. for 2 hours. Theresulting slurry was cooled to room temperature and the slurry wasfiltered. The wet cake was washed with 3×20 mL of water and dry undervacuum to obtain 5.30 g off white solid. Yield: 95%. Form B wasidentified and confirmed by s corresponding XRPD pattern, FT-IR andthermal parameters.

Example 3 Preparation of Form A of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl-N-2-(isopropylsulfonyl)phenyl)-2,4-diamineby seeding a suspension of Form B of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl-N-2-(isopropylsulfonyl)phenyl)-2,4-diaminewith Form A

A small amount of crystalline form A of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine(0.1-1.0% by weight) was added to a suspension of crystalline form B of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diaminein aqueous acetone with stirring at room temperature. The crystallineform was analyzed by its corresponding turbidity profile or by XRPD. Theamount of substantially pure form A obtained is influenced by thesolvent, ratio of acetone to water by volume and the amount of “seed” Aused, as summarized in Table 1.

TABLE 1 Seeding of Crystalline Form B with Form A. Solvent System Form A“Seed” XRPD after Acetone: water (v/v) (weight %) 24 hours 1:9 1.0 FormB + Form A 1:9 0.1 Form B 3:7 1.0 Form A 3:7 0.1 Form B + Form A 1:1 1.0Form A (at 2 hours) 1:1 0.1 Form A (at 4 hours)

Example 4 Conversion of Form B of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamineto Form A of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-isopropylsulfonyl)phenyl)-2,4-diamineby heating in an aqueous solvent

A suspension of crystalline from B of5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diaminewas heated in an aqueous solvent with stirring. The conversion ofcrystalline form B to crystalline form A was analyzed by itscorresponding turbidity profile or by XRPD. The amount of substantiallypure form A obtained and its corresponding time of conversion isinfluenced by the solvent system and temperature, as summarized in Table2.

TABLE 2 Conversion of Crystalline Form B to Crystalline Form A. SolventSystem Temp. Conv. Time Induction Time Yield (v/v) (° C.) (hours)(hours) (%) 1:1 acetone:water 35 >3 — — 1:1 acetone:water 40 2 1 99.11:1 acetone:water 50 1.5 0.1 97.6 1:1 ethanol:water 35 2 38 >99 1:1ethanol:water 50 1 4 >99

1. A method for the treatment of disorders mediated by anaplasticlymphoma kinase, comprising administering to a patient in need of suchtreatment an effective amount of a substantially pure crystalline formof5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine according to claim
 1. 2. The method of claim 1 wherein thedisorder is a cancer selected from anaplastic large cell lymphoma;non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; aneuroblastoma; sarcoma; lung; bronchus; prostate; breast (includingsporadic breast cancers and sufferers of Cowden disease); pancreas;gastrointestinal cancer; colon; rectum; colon carcinoma; colorectaladenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenalgland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma;kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix;vagina; ovary; multiple myeloma; esophagus; a leukemia; acutemyelogenous leukemia; chronic myelogenous leukemia; lymphocyticleukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavityand pharynx; larynx; small intestine; and melanoma.